The primary objective of this proposal is to investigate the genetic regulatory network underlying mammary development and tumorigenesis. Breast cancer is one of the most deadly and preventable diseases among women. Many comprehensive studies have indicated that parity affects the chances of being inflicted with breast cancer. This suggests that parity-dependent alterations significantly remodel the breast tissues and cells. In mice, mammary glands can be regenerated by transplantation of epithelial components, suggesting the existence of mammary stem cells. Their pluripotency further implies that mammary stem cells are involved in cancer development. We hypothesize that alterations in the stem cell population and characteristics contribute to the fundamental changes of mammary glands in life. In the previously proposed investigation, we were able to develop several genetically modified mouse models for the analysis of mammary stem/progenitor cells at various developmental stages. Our studies indicate that the evolutionary conserved Wnt pathway is extremely crucial for stem cell regulation in different phases of mammogenesis. Aberrant regulation of this pathway contributes to the neoplastic transformation of the mammary gland. Previous study also identified Gpr177 which is required for proper functioning of the Wnt pathway. This led to a hypothesis that reciprocal regulation of Wnt and Gpr177 is essential for breast development and disease. In this proposal, we will continue our investigation on the genetic circuitry of Wnt using several sophisticated mouse genetic models. First, we will define Wnt/?-catenin signaling in survival, proliferation and differentiation of stem cells during embryonic mammogenesis and mammary remodeling. Next, we will test if alterations of the stem cell fate contribute to the Wnt-induced tumorigenesis. Finally, we will elucidate the mechanism underlying the reciprocal regulation of Wnt and Gpr177. Genetic analysis in mice will assess the requirement of the Wnt-Gpr177 regulatory circuit in mammary development and cancer. By continuing to delineate the details of Wnt-mediated mammary organogenesis and pathogenesis, this proposal has potential to advance our knowledge base of stem cell biology and cancer biology, leading to novel therapeutic strategies for the treatment of human diseases. PUBLIC HEALTH RELEVANCE: This proposal investigates the basic genetic elements for the formation of breast in health and disease. Using genetically modified mouse strains and breast stem cells, we investigate the importance of Wnt pathway during normal development and pathogenesis of the breast. The results obtained in our study are highly relevant to the health of human breasts, and has outstanding potentials to gain important insights into potential therapeutic strategies for human diseases.